Vildagliptin/pioglitazone combination improved the overall glycemic control in type I diabetic rats.

Type I diabetes (TID) is generally assumed to be caused by an immune associated, if not directly immune-mediated, destruction of pancreatic ß-cells. In patients with long-term diabetes, the pancreas lacks insulin-producing cells and the residual ß-cells are unable to regenerate. Patients with TID are subjected to a lifelong insulin therapy which shows risks of hypoglycemia, suboptimal control and ketosis. In this study, we investigated the potential role of vildagliptin (Vilda) alone or in combination with pioglitazone (Pio), as treatment regimens for TID using streptozotocin (STZ)-induced TID model in rats. Daily oral administration of Vilda (5 mg/kg) alone or in combination with Pio (20 mg/kg) for 7 weeks significantly reduced blood glucose levels and HbA1c. It increased serum insulin levels and decreased serum glucagon. It also showed a strong antioxidant activity. Immunohistochemical analysis showed a marked improvement in ß-cells in treated groups when compared with the diabetic group, which appeared in the normal cellular and architecture restoration of ß-cells in the islets of Langerhans. Vilda alone or in combination with Pio has the ability to improve the overall glycemic control in type I diabetic rats and may be considered a hopeful and effective remedy for TID.

Implication of Nrf2/HO-1 pathway in the coloprotective effect of coenzyme Q10 against experimentally induced ulcerative colitis.

PURPOSE: Given the increased incidence of ulcerative colitis worldwide, the current study was designed to investigate the coloprotective potential of CoQ10 against experimentally induced ulcerative colitis (UC) and specify the implicated mechanisms. METHODS: Ulcerative colitis was induced by intracolonic instillation of [2 ml, 3% v/v acetic acid (AA)]. Rats in the different experimental groups received CoQ10 (10 or 30 and 100 mg/kg, orally) for eight consecutive days, either in a protective or curative regimen. RESULTS: Intracolonic AA instillation significantly increased colon/body weight index, colon weight/colon length ratio, clinical evaluation and macroscopic scoring of UC, serum LDH, C-reactive protein and decreased the serum total antioxidant capacity. Colon MDA, TNF-α and calcium content significantly increased as well, with concomitant reduction in colon GSH, SOD, CAT, Nrf2 and HO-1 contents. Moreover, immunohistochemical staining of colon specimen revealed increased expression of caspase-3 with significant histopathological changes. Coenzyme Q10 suppressed the release of inflammatory biomarkers and restored oxidants/antioxidants hemostasis. In a dose-dependent manner, CoQ10 significantly decreased colon/body weight index, colon weight/colon length ratio, clinical evaluation and macroscopic scoring of UC, serum LDH, C-reactive protein, colon MDA, TNF-α, caspase-3 expression and increased the serum total antioxidant capacity. Colon GSH, SOD, CAT, Nrf2 and HO-1 contents significantly increased. Moreover, coenzyme Q10 significantly preserved tissue histopathological architecture. It appears that the coloprotective effect of CoQ10 was calcium-independent. CONCLUSION: Coenzyme Q10 dose-dependently protects against AA-induced UC mainly via modulation of Nrf2/HO-1 and caspase-3 pathways. Antioxidant, anti-inflammatory and anti-apoptotic properties of CoQ10 are implicated in its observed therapeutic benefit.

Premature Birth, low Birth Weight and Birth Defects after assisted reproductive therapies. a 18-year comparative study.

BACKGROUND: As assisted reproductive therapies (ART) become more common in Tunisia, it was relevant to define the associated perinatal risks. The risk of multiple births and its correlate after ART were well admitted. We aimed to disclose whether ART were associated with increased perinatal risks in singletons and twins from ART comparatively with spontaneous conception. METHODS: A retrospective descriptive and comparative study including all newborns conceived by ART and admitted between 1998 and 2015 and spontaneous newborns selected randomly. We compared separately singletons and twins from ART and natural conception for premature birth (PB) and low birth weight (LBW). For birth defects (BD), we compared the two groups condensed. RESULTS: We identified 425 ART newborns and 322 controls. The risk of PB was statistically higher, in both ART singletons and twins than in controls. Among singletons, the use of ART was associated with statistically significant increased rates of LBW and VLBW. Among twins, this result was valuable only for VLBW. Newborns conceived with ART had a risk of BD that was three times higher than in controls. BD risk was statistically higher with ICSI (Intra Cytoplasm Sperm Injection), ovulation inductor and in vitro fertilization. BD risks were 2.4 times higher with ICSI than with all others therapies condensed. CONCLUSIONS: This study highlighted the increased perinatal risks even in singleton from ART comparatively with natural conception. The exact mechanisms underlying all these risks remain unclear. Further studies are required to prove the part of ART underlying parental factors, and sterility itself.

Congenital diaphragmatic eventration complicated with neonatal gastric perforation.

Congenital diaphragm eventration is a rare and usually asymptomatic developmental defect. Neonatal gastric perforation is also a rare but lifethreatening condition. In our knowledge, the association of these two pathologies has been, exceptionally reported. We report a case who illustrates clinical and radiological features of this possible co-morbidity. A full-term male neonate was born from uneventful pregnancy and delivery. The antenatal scan was reported as normal. At birth, clinical exam was normal, no special resuscitation was necessary. The newborn was examined and admitted the 4th day of life for fever, tachypnea, cyanosis, hemodynamic shock and refusing feeds. Clinical examination suggested peritonitis. Chest radiography and ultrasonography suggested congenital hernia. A laparotomy was performed after a brief resuscitation and confirmed the presence of diaphragm eventration with gastric perforation. Suturing of gastric perforation with a diaphragmatic plication was performed with favorable evolution.

Inherited ADMATS13 deficiency: When to evoke the in the newborn?

Inherited ADMATS13 or Upshaw-Schulman syndrome (USS) is caused by the deficiency of the Von Willebrand factor-cleaving protease. It is characterized by recurrent episodes of thrombocytopenia reversible by fresh frozen plasma (FFP) infusions, microangiopathic hemolytic anemia, and microvascular thrombosis leading to ischemic damage of multiple organs with end stage renal failure, or neurological sequelae in the absence of appropriate treatment. The typically reported features of USS in neonates are severe jaundice with hyperbilirubinemia, thrombocytopenia and /or combs negative hemolytic anemia, and an increased creatinine.We presented a clinical case of USS with unusual features, which delayed the diagnosis.USS was declared at sixth hours of life with diffuse hemorrhage related to an early neonatal infection. Analysis of the plasma, at the age of 20 months, revealed low ADAMTS13 activity in the patient (<1%).Inherited ADMATS13 deficiency manifestations may overlap with other conditions, which may delay diagnosis and lead to visceral and neurological damage. The diagnosis should be, early considered in some clinical conditions: discrepancy between the severity of a hemorrhagic syndrome and thrombocytopenia, recurrence, resistance to symptomatic treatment. The diagnosis can be suggested by the normalization of platelet count after FFP transfusions.

Acute Chest Pain of Coronary Origin in Patients without Diabetes: How Multidetector Computed Tomography (MDCT) Angiography Helps in Diagnosis.

BACKGROUND: To assess the diagnostic value of MDCT coronary angiography for evaluation of acute chest pain of coronary origin in non-diabetic patients. MATERIAL/METHODS: In 22 patients without DM, we assessed coronary arteries with multidetector CT angiography and invasive conventional angiography. RESULTS: CT coronary angiography revealed positive coronary artery disease findings in 16 patients; LAD was affected in 16 (72.3%), RCA in 14 (63.3%), and LCX in 8 (36.4%) cases. The proximal part of LAD was the most commonly affected coronary artery (14 cases, 63.3%) in the studied patients who underwent MSCT coronary angiography. As regards the calcium score, 4 patients (18%) had low calcium scores, 6 cases (27%) had moderate calcium scores, and 12 cases (55%) had high calcium scores. There were 6 patients with positive findings of coronary artery disease detected on MDCT coronary angiography that were not mirrored by conventional angiography. CONCLUSIONS: MDCT angiography of the coronaries is a good and rapid method for evaluation of the coronary anatomy and for early detection and grading of coronary lesions in non-diabetic patients.

Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats.

The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-α) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-α.

Povidone Iodine Pleurodesis for Refractory Congenital Chylothorax: A Review of Literature.

BACKGROUND: Povidone iodine (PVI) pleurodesis is commonly used in adult. However, this procedure is still nonconsensual in newborns. AIMS: This article aimed to report a new case of refractory congenital chylothorax (CCT) managed with PVI pleurodesis with a review of previousreported cases. METHODS: a systematic review of similar cases published in PubMed. Clinical patterns, therapeutic modalities and outcome variables werereported. RESULT: In a full term neonate presenting refractory CCT, PVI pleurodesis was performed at day 16 of life by one intrapleural instillation of PVI4% with rapid success and no side effects. Renal function and thyroid tests stilled normal before and after instillation. The analysis of 18 casesreported in Medeline and our observation provided the following data: this procedure was successful without side effects in 11/19 cases. Severeside effects were reported in four patients with high risks before procedure. CONCLUSION: PVI pleurodesis seems to be effective and inoffensive in the management of refractory CCT. It may be a good alternative tosurgery. Nevertheless, randomized studies on large neonatal population are required to precise: the risks and benefits of this procedure, thetiming and the modalities of its realization (duration of intervention, dilution and dosage of PVI) according to the patient`s field (gestational age,weight and associated morbidity).

The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi.

Thrombosis promotes leukocyte infiltration into inflamed tissues, leading to organ injury in a broad range of diseases; however, the mechanisms by which thrombi guide leukocytes to sites of vascular injury remain ill-defined. Using mouse models of endothelial injury (traumatic or ischemia reperfusion), we demonstrate a distinct process of leukocyte recruitment, termed "directed intravascular migration," specifically mediated by platelet thrombi. Single adherent platelets and platelet aggregates stimulated leukocyte shape change at sites of endothelial injury; however, only thrombi were capable of inducing directed intravascular leukocyte migration. Leukocyte recruitment and migration induced by platelet thrombi occurred most prominently in veins but could also occur in arteries following ischemia-reperfusion injury. In vitro studies demonstrated a major role for platelet-derived NAP-2 (CXCL-7) and its CXCR1/2 receptor in regulating leukocyte polarization and motility. In vivo studies demonstrated the presence of an NAP-2 chemotactic gradient within the thrombus body. Pharmacologic blockade of CXCR1/2 as well as genetic deletion of NAP-2 markedly reduced leukocyte shape change and intrathrombus migration. These studies define a distinct process of leukocyte migration that is initiated by homotypic adhesive interactions between platelets, leading to the development of an NAP-2 chemotactic gradient within the thrombus body that guides leukocytes to sites of vascular injury.

Cervical spondylotic myelopathy: the prediction of outcome following surgical intervention in 93 patients using T1- and T2-weighted MRI scans.

INTRODUCTION: Cervical spondylotic myelopathy (CSM) can lead to significant disability through a spectrum of clinical manifestations ranging from dexterity loss to more profound weakness, incontinence and paralysis. AIM: To determine the outcome of surgical decompression for CSM and investigate pre-operative predictors of outcome. METHODS: Prospectively collected data on all patients who underwent decompressive surgery for CSM and completed 12-month follow-up were reviewed. Data on age, MRI T1 and T2 signal changes pre-operatively, surgical approach and the Nurick's Myelopathy Grade (NMG) was analysed pre-operatively and 1 year post-surgery. RESULTS: Data on 93 consecutive patients who underwent surgery for CSM were reviewed. Median age was 62 (23-94) years and 59% were male. The median follow-up was 37 (17-88) months. The approach was anterior in 38 (42%) patients, posterior in 55 (58%); improvement was not significantly different when the two groups were compared. The number of levels decompressed increased with age (p value <0.0001). The group with a pre-operatively high signal on T1-weighted MRI images [n = 28 (30%)] was associated with less neurological recovery post-operatively compared to the patients with a normal T1 cord signal. None of the patients deteriorated neurologically post-operatively, while 66% improved by at least one NMG. CONCLUSION: Surgical decompressions for CSM stop the progress of symptoms at 12 months post-surgery and may result in a significant improvement of NMG in two-thirds of the patients. Changes in the T1-weighted MRI images predict worse outcomes following surgery.

Degenerative change at the pseudarthrosis after trapeziectomy at 6-year followup.

BACKGROUND: Simple trapeziectomy has a well-documented history of success for the management of osteoarthritis at the trapeziometacarpal joint. There is concern, however, that late-onset failure can occur as a result of the development of degenerative disease at the scaphoid-metacarpal pseudarthrosis. QUESTIONS/PURPOSES: The purpose of this study was to determine whether (1) radiographic changes of degenerative joint disease progressed; (2) the pseudarthrosis height diminished between 1 year and 6 years after either simple trapeziectomy or trapeziectomy with ligament reconstruction and tendon interposition (LRTI); and 3) the presence of degenerative changes were associated with inferior scores on standardized outcomes instruments. METHODS: Using cases from an earlier randomized trial, the 1-year and 6-year stress radiographs of the pseudarthrosis between the distal pole of the scaphoid and the base of the thumb metacarpal were assessed for degenerative change in 25 thumbs that had undergone simple excision of the trapezium and 29 that had undergone trapeziectomy + LRTI for painful trapeziometacarpal joint osteoarthritis. Degenerative change was graded according to a Kellgren and Lawrence system, and clinical results were assessed using the Patient Evaluation Measure (PEM), Disabilities of the Arm, Shoulder and Hand (DASH) questionnaires, and thumb key pinch strength. RESULTS: One of the 29 thumbs treated with trapeziectomy + LRTI and seven of the 25 thumbs treated by simple excision of the trapezium exhibited increased degenerative change at their final followup. A pseudarthrosis space was preserved in 22 of the 25 simple trapeziectomies and 28 of the 29 trapeziectomies + LRTI. The presence of degenerative change did not adversely affect the outcome as measured by the PEM, the DASH, or thumb key pinch strength. CONCLUSIONS: Increased degenerate-like changes were observed after simple excision of the trapezium but these did not influence the clinical outcome. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets.

BH3 mimetics are a new class of proapo-ptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the pro-survival function of one or more Bcl-2-related proteins. Agents that inhibit Bcl-x(L) induce rapid platelet death that leads to thrombocytopenia; however, their impact on the function of residual circulating platelets remains unclear. In this study, we demonstrate that the BH3 mimetics, ABT-737 or ABT-263, induce a time- and dose-dependent decrease in platelet adhesive function that correlates with ectodomain shedding of the major platelet adhesion receptors, glycoprotein Ibα and glycoprotein VI, and functional down-regulation of integrin α(IIb)ß(3). Analysis of platelets from mice treated with higher doses of BH3 mimetics revealed the presence of a subpopulation of circulating platelets undergoing cell death that have impaired activation responses to soluble agonists. Functional analysis of platelets by intravital microscopy revealed a time-dependent defect in platelet aggregation at sites of vascular injury that correlated with an increase in tail bleeding time. Overall, these studies demonstrate that Bcl-x(L)-inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets.

A standardized pomegranate fruit extract ameliorates thioacetamide-induced liver fibrosis in rats via AGE-RAGE-ROS signaling.

This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-ß1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-ß1, and TIMP-1.

Nifuroxazide mitigates doxorubicin-induced cardiovascular injury: Insight into oxidative/NLRP3/GSDMD-mediated pyroptotic signaling modulation.

Doxorubicin (DOX) is a widely used powerful anthracycline for treatment of many varieties of malignancies; however its cumulative and dose-dependent cardio-toxicity has been limited its clinical use. In the current study, in vivo and in vitro (neonatal rat's cardiomyocytes) experiments were conducted to identify the impact of nifuroxazide (NIFU) on DOX-induced cardiomyopathy, vascular injury, and hemato-toxcity and plot the underlying regulatory mechanisms. Cardiovascular injury was induced in vivo by I.P. injection of an overall dose of DOX (21 mg/kg) administered (3.5 mg/kg) twice weekly for 21 days. NIFU (10 and 30 mg/kg) was administered orally once daily for 21 days, 1 week after DOX injection initiation. In vivo experiments confirmed NIFU to restore blood cells counts and hemoglobin concentration. Moreover, NIFU normalized the myocardial functional status as confirmed by ECG examination and myocardial injury markers; CK-MB, LDH, and AST. NIFU restored the balance between TAC and both of ROS and MDA and down-regulated the protein expression of TLR4, NF-kB, TXNIP, NLR-family pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, and GSDMD-N terminal, with inhibition of the up-stream of NLRP3 and the down-stream DOX-induced pyroptosis. The in vitro assay confirmed well preserved cardiomyocytes' architecture, amelioration of NLRP3/IL-1 ß-mediated cell pyroptosis, enhanced cell viability, and improved spontaneous beating. Moreover, NIFU normalized the disturbed aortic oxidant-antioxidant balance; enhanced eNOS- mediated endothelial relaxation, and down regulated IL-1ß expression. Thus, NIFU may be proposed to serve as a cardioprotective agent to attenuate DOX-induced cardio-toxicity and vascular injury.

PI 3-kinase p110beta: a new target for antithrombotic therapy.

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.

Dose-dependent renoprotective impact of Lactoferrin against glycerol-induced rhabdomyolysis and acute kidney injury.

Acute kidney injury (AKI) is a clinical disorder with a serious impact on the quality of patients' lives. Considering its increased worldwide prevalence, investigating novel therapeutic approaches for the management of AKI has been inevitable. Lactoferrin (LF), a glycoprotein belonging to the transferrin family, is known to play an important role in regulating iron homeostasis. This study aimed to evaluate the renoprotective effect of LF (30, 100, and 300 mg/kg orally) against glycerol (GLY)-induced rhabdomyolysis (RM) in rats. RM was induced by a single intramuscular injection of GLY 50% (10 mL/kg) after 24-h water deprivation in male Sprague-Dawley rats. LF administration conferred significant dose-dependent renoprotective impact against GLY-induced RM as evidenced by the decreased renal/somatic index and the significant improvement in renal functions as confirmed by the significant increase in creatinine clearance, decrease in serum creatinine and blood urea nitrogen, and improvement in albuminuria and proteinuria. Redox homeostasis was significantly restored in a dose-dependent manner as well. Moreover, serum interleukin-1ß (IL-1ß) was significantly decreased with a parallel significant decrease in renal NOD-like receptor family pyrin domain containing 3 (NLRP3) and thioredoxin interacting protein (TXNIP), kidney injury molecule-1 (KIM-1), caspase-3 expression, nuclear factor kappa B (NF-κB), cluster of differentiation (CD68) expression, and a significant increase in renal nuclear factor erythroid 2-related factor 2 (NRF2) expression. Ultimately, LF administration was associated with a significant amelioration of GLY-induced renal necrotic and inflammatory alterations. In conclusion, the observed dose-dependent nephroprotective effect of LF can be attributed to its modulatory impact on inflammatory/apoptotic/oxidative signaling.

Indapamide Increases IRS1 Expression and Modifies Adiponectin/NLRP3/PPARγ Crosstalk in Type 2 Diabetic Rats.

The current study aimed to evaluate the anti-diabetic effects of canagliflozin (CANA) and indapamide (INDA) and their impacts as adiponectin modulators in experimentally induced type 2 diabetes mellitus (T2DM). T2DM was associated with a significant rise in blood glucose level and HbA1C%, andreduced adiponectin and insulin secretions. Moreover, the malondialdehyde (MDA) contents in both the epididymal adipocytes and soleus muscle significantly escalated, while the total antioxidant capacity (TAC) and epididymal adipocyte Nrf2 expression significantly declined. Moreover, serum TNF-α, epididymal adipocyte's NOD-like receptor protein 3, NLRP3, NF-κB and CD68 expressions markedly escalated, and serum IL-10 significantly declined. Furthermore, there was a significant escalation in PPARγ expression in epididymal adipocytes, with a significant reduction in soleus muscle's expression of IRS1. CANA and INDA treatments markedly reduced blood glucose levels, increased adiponectin and insulin secretion, enhanced anti-oxidant defenses, and reduced oxidative burden, with marked anti-inflammatory impact. Interestingly, the impact of indapamide on DM indices and oxidative and inflammatory changes was comparable to that of canagliflozin. Nevertheless, indapamide had a superior effect compared to canagliflozin on HbA1c%, expression of IRS1 and reduction of NF-κB and CD68 expressions. INDA could be effective in regulating T2DM, with underlined anti-diabetic, antioxidant, and anti-inflammatory properties. INDA increased IRS1 expression and modified adiponectin/NLRP3/PPARγ crosstalk. The impacts of INDA are comparable to those of the standard anti-diabetic drug CANA.

Clinical and Radiographic Outcomes of Revision Total Ankle Arthroplasty Using the INBONE II Prosthesis.

BACKGROUND: The literature on the outcome of revision total ankle arthroplasty (TAA) remains limited. In this study, we aimed to report the clinical and radiographic outcomes of revision TAA at a high-volume center in the United Kingdom. METHODS: This study was a retrospective review of 28 patients who underwent 29 revision TAAs using the INBONE II Total Ankle System (Wright Medical Technology/Stryker). Demographic, radiographic, and patient-reported outcome measure data were analyzed. RESULTS: The mean duration from primary TAA to revision was 87.5 months (range, 16 to 223 months). The main indication for the revision was aseptic loosening after the primary TAA (83%). Additional procedures were required in 76% of ankles. At a mean follow-up of 40 months (range, 24 to 60 months), the infection rate was 7%, the reoperation rate was 7%, and the implant survival rate was 97%. A significant postoperative improvement in the radiographic component alignment measures was observed. The subsidence, loosening, and heterotopic ossification rates in this study were comparable with those in other reports and did not influence the clinical outcome. A significant improvement was observed in the Manchester-Oxford Foot Questionnaire (MOXFQ) in all domains and the EuroQol-5 Dimensions (EQ-5D) in 3 domains at 24 months postoperatively. CONCLUSIONS: Revision TAA using the INBONE II prosthesis was associated with good short-term survival and improvement in postoperative scores at 2 years. Maintenance of the postoperatively improved alignment was documented at the follow-up. The results of this study support the notion that revision TAA is a satisfactory option for failed primary TAA. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Diacerein versus adipoRon as adiponectin modulators in experimentally-induced end-stage type 2 diabetes mellitus in rats.

The objective of the present study is to evaluate and compare the possible anti-diabetic effects of adipoRon and diacerein in type 2 diabetes mellitus (T2DM) rats. T2DM is marked by impaired oxidative, inflammatory and metabolic signaling. Indeed, T2DM progression is associated with elevated HbA1C%, low adiponectin and insulin concentration. Moreover, in this study epididymal adipose tissue and soleus muscle MDA contents significantly escalated, while serum TAC and epididymal adipose Nrf2 significantly declined. Nevertheless, serum TNF-α, epididymal NLRP3, NF-κB, PPARγ and CD68 expression rose significantly with a parallel significant reduction in serum IL-10 and soleus muscle expression of IRS1. Both adipoRon and diacerein significantly improved adiponectin and insulin secretion with augmentation of anti-oxidant defenses and diminution of oxidative burden, with obvious anti-inflammatory consequences (p < 0.05). Thus, adipoRon and diacerein positively modulated adiponectin expression with down-regulation of NF-κB/NLRP3/PPARγ expression with subsequent improvement in glycemic control, inflammatory and oxidative signaling.

Calycosin modulates NLRP3 and TXNIP-mediated pyroptotic signaling and attenuates diabetic nephropathy progression in diabetic rats; An insight.

Diabetic nephropathy [DN] is one of the most prevalent microvascular complications of diabetes mellitus [DM] and it is considered a leading cause of kidney failure. In this study calycosin, an isoflavone that constitutes the major constituent in Radix Astragali with numerous pharmacological merits was investigated as reno-protective agent against DN and also the potential underlying mechanisms were investigated. Streptozotocin (STZ) (40 mg/kg) was injected in the peritoneal cavity of male Sprague-Dawely rats to induce DM. For ten weeks, calycosin (5 and 10 mg/kg), and NAC (500 mg/kg) were orally administered and they significantly lowered blood glucose levels, but significantly increased insulin levels. Calycosin improved the deteriorated kidney functions as evidenced in retracted serum creatinine, albuminuria, blood urea nitrogen, and proteinuria levels. Meanwhile, urine creatinine clearance significantly escalated. Furthermore, biomarkers of cell injury; LDH activity, significantly declined and kidney content of NO markedly decreased as well. Inflammation, fibrosis and oxidative stress were manifested by increased serum levels of IL-1ß, renal NF-κBp65, NLRP3, TXNIP and MDA contents with declined levels of IL-10 and TAC and decreased Nrf2 expression. The above-mentioned biomarkers were significantly improved with calycosin treatment which modulated NF-κB/p65/NLRP3/TXNIP signaling, oxidative stress, inflammatory cytokines and fibrotic processes; Thus, implying a reno-protective impact. This was associated with improvement in renal histopathological and immune-histopathological parameters; H&E, Masson Trichrome and Nrf-2. Based on these findings, calycosin can be presumed to be a promising drug for hindering the development of DN through modulation of NF-κB/p65/NLRP3/TXNIP inflammasome signaling pathway.